1-(2-(morpholin-4-yl)-5-trifluoromethylphenyl)-3-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea | 1160825-53-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 1-(2-(morpholin-4-yl)-5-trifluoromethylphenyl)-3-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea
• 英文别名: 1-[2-Morpholin-4-yl-5-(trifluoromethyl)phenyl]-3-[4-[(2-oxo-1,3-dihydroimidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea
• CAS: 1160825-53-5
• 化学式: C₂₈H₂₃F₃N₆O₄
• 分子量: 564.524
• InChiKey: DZFSGHUSRGJTTD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  41
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  117
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  7-((4-aminonaphthalen-1-yl)oxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one 、 2-(morpholin-4-yl)-5-(trifluoromethyl)phenyl isocyanate 以 四氢呋喃 为溶剂， 反应 14.0h， 以71%的产率得到1-(2-(morpholin-4-yl)-5-trifluoromethylphenyl)-3-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea
  参考文献：
  名称：

  Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring

  摘要：

  BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number Of Substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogqnic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC50 of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.

  DOI：

  10.1021/jm900242c

文献信息

• Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring
  作者：Delphine Ménard、Ion Niculescu-Duvaz、Harmen P. Dijkstra、Dan Niculescu-Duvaz、Bart M. J. M. Suijkerbuijk、Alfonso Zambon、Arnaud Nourry、Esteban Roman、Lawrence Davies、Helen A. Manne、Frank Friedlos、Ruth Kirk、Steven Whittaker、Adrian Gill、Richard D. Taylor、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm900242c

  日期：2009.7.9

  BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number Of Substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogqnic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC50 of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.